Studies have shown that maternal exposure to cigarette smoke during pregnancy correlates significantly with adverse conceptus development, especially fetal growth restriction (FGR). In addition to obstetrical complications, FGR has been implicated in long-term effects on adult health, morbidity and even mortality. To elucidate the mechanisms of cigarette smoke-induced FGR we will use samples of placentae, maternal blood and cord blood from smoking and non-smoking pregnancies whose degree of FGR are known. Our hypothesis is that alteration of human growth factor genes, specifically insulin-like growth factor-1 (IGF-1), can be induced by environmental exposure to cigarette smoke toxins and produce FGR when the expressed abnormal gene products fail to properly regulate growth and development. Smoking-related gene alterations (polymorphisms) can result from the failure of enzymes required for detoxification of toxins coupled with enzymatic activation to reactive products that bind with DNA (adduct formation). This leads to DNA polymorphism and expression of abnormal gene products. The primary focus of our studies will be IGF-1. Placental IGF-1 gene will be assessed for polymorphism and alteration of nucleic acid sequences. IGF-1 gene expression products in maternal and cord blood will be determined and characterized. Adduct formation between activated toxins and the placental IGF-1 gene will be assessed. Since the process of detoxification versus activation involves specific enzymes, these will be measured in affected and non-affected pregnancies from smoking and non-smoking mothers (controlled by serum nicotine and cotinine assays) by assessing detoxification or activation of polynuclear aromatic hydrocarbons (PAH) into reactive products that bind with DNA. Similar studies will be performed on cultured chorionic villus sample cells from first trimester (CVS). Finally, by genotyping of the IGF-1 gene in the first trimester (CVS) and post delivery placentas during the same pregnancy we will determine both early and late effects of smoking, and identify pregnancies with high risk of smoking-induced FGR. If successful, such testing could be of considerable clinical utility. [unreadable] [unreadable]